NM_003865.3:c.478C>T

Variant names:

• chr3-57198277-G-A
• rs28936702
• NM_003865.3:c.478C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_003865.3(HESX1):​c.478C>T​(p.Arg160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,460,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: HESX1 NM_003865.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.82

Genes affected

HESX1 (HGNC:4877): (HESX homeobox 1) This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-57198277-G-A is Pathogenic according to our data. Variant chr3-57198277-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7691.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-57198277-G-A is described in Lovd as [Likely_pathogenic]. Variant chr3-57198277-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3	c.478C>T	p.Arg160Cys	missense_variant	Exon 4 of 4	ENST00000295934.8	NP_003856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HESX1	ENST00000295934.8	c.478C>T	p.Arg160Cys	missense_variant	Exon 4 of 4	1	NM_003865.3	ENSP00000295934.3
HESX1	ENST00000647958.1	c.478C>T	p.Arg160Cys	missense_variant	Exon 7 of 7			ENSP00000498190.1
HESX1	ENST00000473921.2	c.376C>T	p.Arg126Cys	missense_variant	Exon 3 of 3	5		ENSP00000418918.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250912 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460524 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000307 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES Pathogenic:1

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the HESX1 protein (p.Arg160Cys). This variant is present in population databases (rs28936702, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive septo-optic dysplasia (PMID: 9620767, 25500790, 27000987, 33098107). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg53Cys. ClinVar contains an entry for this variant (Variation ID: 7691). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HESX1 function (PMID: 9620767, 11748154, 19093031, 25910213). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Septo-optic dysplasia sequence Pathogenic:1

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.5	.;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.81, 0.75
MutPred		0.97		Loss of disorder (P = 0.0149);Loss of disorder (P = 0.0149);.;
MVP		1.0
MPC		0.41
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28936702; hg19: chr3-57232305;